The interaction of comorbidities, aging, and HIV persistence in tissues

PURPOSE OF REVIEW: The review examines the how the HIV reservoir and its tissue distribution intersect with aging and comorbidity development in people with HIV (PWH) on suppressive antiretroviral therapy (ART) and considers implications for cure-directed research in an aging population. RECENT FINDINGS: PWH on ART carry a disproportionate and accelerating comorbidity burden, with multimorbidity projected to rise from 63 to 70% by 2030. Neurocognitive disorders, liver disease, lung disease, cardiovascular disease, and frailty are all elevated, and linked to the viral reservoir through chronic inflammation and direct viral mechanisms. Coinfections (HCV, HBV, CMV) compound this issue by amplifying the reservoir while independently driving the same comorbidities, particularly liver disease, and cardiovascular and frailty outcomes. SUMMARY: Reservoir persistence and comorbidity burden in aging PWH are mechanistically intertwined, with chronic inflammation as a common driver. These findings underscore the need for longitudinal, tissue-resolved studies spanning the lifespan, as well as inclusion of aged and comorbid individuals in cure-directed trials, given that immune-engagement-dependent cure strategies may exhibit differential efficacy in this growing population.